Phosphoryl transferases are a large family of enzymes that transfer phosphorous-containing groups from one substrate to another. Kinases are a class of enzymes that function in the catalysis of phosphoryl transfer. The protein kinases constitute the largest subfamily of structurally related phosphoryl transferases and are responsible for the control of a wide variety of signal transduction processes within the cell. Almost all kinases contain a similar 250-300 amino acid catalytic domain. The protein kinases may be categorized into families by the substrates they phosphorylate (e.g., protein-tyrosine, protein-serine/threonine, etc.). Protein kinase sequence motifs have been identified that generally correspond to each of these kinase families. Lipid kinases (e.g. PI3K) constitute a separate group of kinases with structural similarity to protein kinases.
The “kinase domain” appears in a number of polypeptides which serve a variety of functions. Such polypeptides include, for example, transmembrane receptors, intracellular receptor associated polypeptides, cytoplasmic located polypeptides, nuclear located polypeptides and subcellular located polypeptides. The activity of protein kinases can be regulated by a variety of mechanisms. It must be noted, however, that an individual protein kinase may be regulated by more than one mechanism. These mechanisms include, for example, autophosphorylation, transphosphorylation by other kinases, protein-protein interactions, protein-lipid interactions, protein-polynucleotide interactions, ligand binding, and post-translational modification.
Protein and lipid kinases regulate many different cell processes including, but not limited to, proliferation, growth, differentiation, metabolism, cell cycle events, apoptosis, motility, transcription, translation and other signaling processes, by adding phosphate groups to targets such as proteins or lipids. Phosphorylation events catalyzed by kinases act as molecular on/off switches that can modulate or regulate the biological function of the target protein. Phosphorylation of target proteins occurs in response to a variety of extracellular signals (hormones, neurotransmitters, growth and differentiation factors, etc.), cell cycle events, environmental or nutritional stresses, etc. Protein and lipid kinases can function in signaling pathways to activate or inactivate, or modulate the activity of (either directly or indirectly) the targets. These targets may include, for example, metabolic enzymes, regulatory proteins, receptors, cytoskeletal proteins, ion channels or pumps, or transcription factors. Uncontrolled signaling due to defective control of protein phosphorylation has been implicated in a number of diseases and disease conditions, including, for example, inflammation, cancer, allergy/asthma, disease and conditions of the immune system, disease and conditions of the central nervous system (CNS), cardiovascular disease, dermatology, and angiogenesis.
Initial interest in protein kinases as pharmacological targets was stimulated by the findings that many viral oncogenes encode structurally modified cellular protein kinases with constitutive enzyme activity. These findings pointed to the potential involvement of oncogene related protein kinases in human proliferative disorders. Subsequently, deregulated protein kinase activity, resulting from a variety of more subtle mechanisms, has been implicated in the pathophysiology of a number of important human disorders including, for example, cancer, CNS conditions, and immunologically related diseases. The development of selective protein kinase inhibitors that can block the disease pathologies and/or symptoms resulting from aberrant protein kinase activity has therefore generated much interest.
Protein kinases represent a large family of proteins which play a central role in the regulation of a wide variety of cellular processes, maintaining control over cellular function. A partial list of such kinases includes abl, AKT, bcr-abl, Blk, Brk, Btk, c-kit, c-met, c-src, CDK1, CDK2, CDK3, CDK4, CDK5, CDK6, CDK7, CDK8, CDK9, CDK10, cRaf1, CSFir, CSK, EGFR, ErbB2, ErbB3, ErbB4, Erk, Fak, fes, FGFR1, FGFR2, FGFR3, FGFR4, FGFR5, Fgr, flt-1, Fps, Frk, Fyn, Hck, IGF-1R, INS-R, Jak, KDR, Lck, Lyn, MEK, p38, PDGFR, PIK, PKC, PYK2, ron, tie, tie2, TRK, Yes, and Zap70. Inhibition of such kinases has become an important therapeutic target.
A major feature of malignant cells is the loss of control over one or more cell cycle elements. These elements range from cell surface receptors to the regulators of transcription and translation, including the insulin-like growth factors, insulin growth factor-I (IGF-1) and insulin growth factor-2 (IGF-2). [M. J. Ellis, “The Insulin-Like Growth Factor Network and Breast Cancer”, Breast Cancer, Molecular Genetics, Pathogenesis and Therapeutics, Humana Press 1999]. The insulin growth factor system consists of families of ligands, insulin growth factor binding proteins, and receptors. A major physiological role of the IGF-1 system is the promotion of normal growth and regeneration, and overexpressed IGF-1R can initiate mitogenesis and promote ligand-dependent neoplastic transformation. Furthermore, IGF-1R plays an important role in the establishment and maintenance of the malignant phenotype.
IGF-1R exists as a heterodimer, with several disulfide bridges. The tyrosine kinase catalytic site and the ATP binding site are located on the cytoplasmic portion of the beta subunit.
Unlike the epidermal growth factor (EGF) receptor, no mutant oncogenic forms of the IGF-1R have been identified. However, several oncogenes have been demonstrated to affect IGF-1 and IGF-1R expression.
The correlation between a reduction of IGF-1R expression and resistance to transformation has been seen. Exposure of cells to the mRNA antisense to IGF-1R RNA, prevents soft agar growth of several human tumor cell lines.
Apoptosis is a ubiquitous physiological process used to eliminate damaged or unwanted cells in multicellular organisms. Disregulation of apoptosis is believed to be involved in the pathogenesis of many human diseases. The failure of apoptotic cell death has been implicated in various cancers, as well as autoimmune disorders. Conversely, increased apoptosis is associated with a variety of diseases involving cell loss such as neurodegenerative disorders and AIDS. As such, regulators of apoptosis have become an important therapeutic target. It is now established that a major mode of tumor survival is escape from apoptosis. IGF-1R abrogates progression into apoptosis, both in vivo and in vitro. It has also been shown that a decrease in the level of IGF-1R below wild-type levels causes apoptosis of tumor cells in vivo. The ability of IGF-1R disruption to cause apoptosis appears to be diminished in normal, non-tumorigenic cells.
WO01/00213, published 4 Jan. 2001, describes substituted pyrimidines as SRC kinase inhibitors. WO01/40218, published 7 Jun. 2001, describes arylamine derivatives for use as anti-telomerase agents. WO00/39101, published 6 Jul. 2000, describes substituted pyrimidines as anti-cancer agents. WO01/29009, published 26 Apr. 2001, describes substituted pyrimidines as kinase inhibitors. WO00/78731, published 28 Dec. 2000, describes cyano substituted pyrimidines as kinase inhibitors. WO00/53595, published 14 Sep. 2000, describes substituted pyrimidines as kinase inhibitors. WO00/39101, published 6 Jul. 2000, describes amino substituted pyrimidines as kinase inhibitors. WO00/59892, published 12 Oct. 2000, describes amino substituted pyrimidines as kinase inhibitors. WO97/19065, published 29 May 1997, describes 2-anilino-pyrimidines as kinase inhibitors. EP379806, published 10 Apr. 1996, describes substituted pyrimidines for the treatment of neurological disorders. EP1040831, published 4 Oct. 2000, describes substituted pyrimidines as CRF antagonists. Amino substituted pyrimidines were cited in Chem. Abstr. 112:191083. Amino substituted pyrimidines were cited in Chem. Abstr. 72:1114009. WO95/33750, published 14 Dec. 1995, describes substituted pyrimidines as CRF antagonists. WO94/26733, published 24 Nov. 1994, describes pyrimidine derivatives as ligands for dopamine receptors. U.S. Pat. No. 5,958,935 describes substituted pyrimidines as kinase inhibitors. U.S. Pat. No. 4,983,608, describes pyrrolyl-amino substituted pyrimidines as analgesic agents. U.S. Pat. No. 5,043,317, describes amino substituted pyrimidines as dyes. U.S. Pat. No. 5,935,966 describes carboxylate substituted pyrimidines as anti-inflammatories. U.S. Pat. No. 6,080,858 describes a process for preparing substituted pyrimidines. WO99/50250, published 7 Oct. 1999, describes amino substituted pyrimidines for the treatment of HIV infection. EP945443, published 29 Sep. 1999, describes amino substituted pyrimidines for the treatment of HIV infection. WO99/31073, published 24 Jun. 1999, describes amide substituted pyrimidines. WO00/27825, published 18 May 2000, describes amino substituted pyrimidines for the treatment of HIV infection. WO01/22938, published 5 Apr. 2001, describes amino substituted pyrimidines for the treatment of HIV infection. WO99/41253, published 19 Aug. 1999, describes amino substituted pyrimidines for the treatment of viral infection. WO01/19825, published 22 Mar. 2001, describes amino substituted pyrimidines as synthetic intermediates. WO01/47921, published 5 Jul. 2001, describes amino substituted pyrimidines as kinase inhibitors. WO01/72745, published 4 Oct. 2001, describes 4-heteroaryl-substituted pyrimidines as inhibitors of CDK's. WO01/72717, published 4 Oct. 2001, describes 4-amino-5-cyanopyrimidines as inhibitors of CDK's. WO01/85700, published 15 Nov. 2001, describes pyrimidines as HIV replication inhibitors. WO02/22601, published 21 Mar. 2002, describes 4-(pyrazol-5-ylamino)pyrimidines as kinase inhibitors. WO02/46184, published describes 4-(4-pyrazolyl)-pyrimidines as kinase inhibitors. WO02/46170, published 13 Jun. 2002, describes 2-anilino-pyrimidines as inhibitors of JNK. WO02/46171, published 13 Jun. 2002, describes 2-anilino-pyrimidines as inhibitors of IKK. WO02/47690, published 20 Jun. 2002, describes 4-arylamino-pyrimidines as kinase inhibitors. WO02/48147, published 20 Jun. 2002, describes pyrimidines as kinase inhibitors. WO02/48148, published 20 Jun. 2002, describes pyrimidines as kinase inhibitors. Ghoneim et al., Egypt J. Pharm. Sci., 28, 117-26 (1987)) describe N,N′-bis(3,5-dimethyl-4-isoxazolyl)-6-methyl-2,4-pyrimidinediamine. Ghoneim et al., J. Indian Chem. Soc., 63, 914-17 (1986)) describe N,N′-bis(3,5-dimethyl-4-isoxazolyl)-6-methyl-2,4-pyrimidinediamine. WO02/50065, published 27 Jun. 2002, describes 2-(5-pyrazolylamino)-pyrimidines as kinase inhibitors. WO02/50066, published 27 Jun. 2002, describes 2-(5-pyrazolylamino)-pyrimidines as kinase inhibitors. WO02/57259, published 25 Jul. 2002, describes 4-(5-pyrazolylamino)-pyrimidines as kinase inhibitors. WO02/59110, published 1 Aug. 2002, describes amino substituted pyrimidines as inhibitors of VEGFR2.
However, compounds of the current invention have not been described as inhibitors for the treatment of cancer.